Mechanistic Insights into Di-2-ethylhexyl Phthalate (DEHP)-Induced Metabolic Disruption: Integrating Gut Hormone Secretion and Metabolomics in Colonic Organoids

Di-2-ethylhexyl phthalate (DEHP), an endocrine-disrupting plasticizer, may interfere with insulin signaling and increase diabetes risk at low concentrations. Predominantly ingested through food, DEHP directly impacts the intestines where gut hormones that regulate blood sugar are produced. Colonic organoids, with their realistic three-dimensional structure, provide a more physiologically relevant model. Our study used mouse colonic organoids to investigate dietary DEHP exposure on gut endocrine function. Results showed that low doses of DEHP promoted secretion of glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and gastric inhibitory polypeptide (GIP), while decreasing cholecystokinin (CCK) secretion. DEHP exposure increased cyclic AMP levels, supporting the secretion of GLP-1, PYY, and GIP, which may enhance insulin secretion. Metabolomic analyses indicated decreased arachidonic acid levels, potentially increasing inflammation risk and inhibiting gallbladder contraction. These results suggest DEHP exposure significantly alters gut hormone secretion and metabolism, disrupting glucose regulation. Further research is needed to fully understand these mechanisms and their implications for diabetes risk.